Obesity is associated with generalized insulin resistance, cardiac hypertrophy and reduced cardiac function. Our preliminary data indicates that these changes are associated with resistance in the heart to the metabolic effects of insulin. Thus our broad hypothesis is that cardiac insulin resistance is characterized by uncoupling of signaling via the PI3-Kinase and MAP Kinase pathways. Early loss of PI3-Kinase signaling results in persistent and even augmented signaling via the MAP Kinase pathway, that coupled with activation of the renin-angiotensin system (RAS) leads to progressive cardiac insulin resistance, cardiac hypertrophy, and ventricular dysfunction. We hypothesize that this will occur through several mechanisms such as reduced expression/activity of eNOS, decreased glucose metabolism, increased fatty acid uptake/oxidation that is not suppressed by ambient hyperinsulinemia and abnormal excitation contraction coupling. Aim 1: will define the time course for the onset of disordered insulin signaling and RAS activation in the hearts of ob/ob mice and determine the impact of these changes on cardiac structure, function and metabolism. Aim 2: will further dissect the contributions of insulin signaling both globally and via the PI3-Kinase pathway by generating 2 novel transgenic mouse models (ob/ob mice with insulin receptor deletion in cardiomyocytes and ob/ob mice with inactivation of PI3 Kinase in cardiomyocytes. Thus loss of PI3-Kinase signaling may accelerate the development of cardiac dysfunction in obesity by augmenting the deleterious consequences of insulin and RAS signaling via MAP Kinase, whereas reduced insulin-mediated MAP Kinase signaling might retard but not necessarily prevent the abnormal cardiac remodeling that results from RAS activation in obesity. Aim 3: will determine the role of pharmacological inhibition of the RAS or activation of the RAS, induced by pressure overload hypertrophy, on the progression of the changes in structure, function and metabolism that characterizes the insulin resistant heart in obesity. Chronic inhibition of the RAS will ameliorate the insulin signaling and metabolic defects in the hearts of obese mice and attenuate LV hypertrophy and cardiac dysfunction. Conversely, activation of the RAS will result in more rapid progression to decompensated heart failure in obese than in lean animals. These studies will provide a detailed and comprehensive analysis of the role that abnormal myocardial insulin signaling plays in the pathogenesis of cardiac dysfunction in obesity.